Our recent work has focused upon studies of the internal motions of the HIV-1 protease (a) free in solution, as a fully active, but stable protease mutant (Q7K, L33I, L63I) (b) complexed with DMP323, a symmetric, specific and potent (Ki ~ 1 nM) inhibitor. We have extended our initial studies of protease backbone dynamics to dynamics of protease sidechains. Methyl group flexibility is of particular interest because nearly 50% of the amino acid residues of HIV-1 protease contain methyl sidechains, most of which appear to be organized in inner (I) and outer (O)clusters. Residues in the I-cluster make up part of the inhibitor binding site, while those in the O-cluster form the hydrophobic core that stabilizes the protein structure. In addition nearly 2/3 of the mutations associated with drug resistance are in methyl containing residues. Using a novel labeling approach that enabled us to record both 13C and 2H relaxation data we observed that many methyl sidechains, in both free and DMP323 bound protease were flexible on fast and slow timescales. Flexible methyl sites, that are partially or fully buried, were found in both methyl clusters as well as in residues that link the clusters. These flexible sites, particularly in the residues that link the clusters, may allow the protease to adjust its conformation in response to the binding of a variety of substrates and to mutations in its amino acid sequence that are selected by drug-treatment. Because the methyl cluster motif appears to be a common structural feature of retroviral proteases, it may play a similar role throughout this family of enzymes. While reasonable, these hypotheses need to be tested by studies of spin relaxation, kinetic parameters and structural stability of mutant proteases selected for drug resistance.